The broad goal of this research is to continue studies of inherited deficiencies of human carbonic anhydrases (CAs) in order to define the physiologic roles of the various members of this gene family, and to define their genetic interrelationships. The specific aims for this project period are four: 1) Define the molecular genetics of carbonic anhydrase II deficiency. (CA II deficiency is the basis for a newly classified inbor error producing osteopetrosis, renal tubular acidosis and cerebral calcification.) 2) Define the molecular genetics of the deficiency of salivary carbonic anhydrase which is seen in patients with CA II deficiency syndrome. 3) Characterize and define the interrelationships of the integral membrane forms of carbonic anhydrase in lung and kidney. 4) Characterize the phenotype and define the molecular basis of CA IV deficiency in man. Those carbonic anhydrases no already purified in our laboratory will be purified, characterized, subjected to microsequencing, and the cDNA genes will be cloned and characterized. In some cases, the genomic DNA specifying the enzymes will be isolated to characterize the genomic organization, gene localization, and the nature of the mutation underlying the altered expression of the carbonic anhydrase gene.